A delphi study to detect deficiencies and propose actions in real life treatment of neovascular age-related macular degeneration.

Purpose. Spanish retina specialists were surveyed in order to propose actions to decrease deficiencies in real-life neovascular age macular degeneration treatment (nv-AMD). Methods. One hundred experts, members of the Spanish Vitreoretinal Society (SERV), were invited to complete an online survey of 52 statements about nv-AMD management with a modified Delphi methodology. Four rounds were performed using a 5-point Linkert scale. Recommendations were developed after analyzing the differences between the results and the SERV guidelines recommendations. Results. Eighty-seven specialists completed all the Delphi rounds. Once major potential deficiencies in real-life nv-AMD treatment were identified, 15 recommendations were developed with a high level of agreement. Consensus statements to reduce the burden of the disease included the use of treat and extend regimen and to reduce the amount of diagnostic tests during the loading phase and training technical staff to perform these tests and reduce the time between relapse detection and reinjection, as well as establishing patient referral protocols to outside general ophthalmology clinics. Conclusion. The level of agreement with the final recommendations for nv-AMD treatment among Spanish retinal specialist was high indicating that some actions could be applied in order to reduce the deficiencies in real-life nv-AMD treatment.

Added Value of Deep Sequencing Relative to Population Sequencing in Heavily Pre-Treated HIV-1-Infected Subjects.

OBJECTIVE: To explore the potential of deep HIV-1 sequencing for adding clinically relevant information relative to viral population sequencing in heavily pre-treated HIV-1-infected subjects. METHODS: In a proof-of-concept study, deep sequencing was compared to population sequencing in HIV-1-infected individuals with previous triple-class virological failure who also developed virologic failure to deep salvage therapy including, at least, darunavir, tipranavir, etravirine or raltegravir. Viral susceptibility was inferred before salvage therapy initiation and at virological failure using deep and population sequencing genotypes interpreted with the HIVdb, Rega and ANRS algorithms. The threshold level for mutant detection with deep sequencing was 1%. RESULTS: 7 subjects with previous exposure to a median of 15 antiretrovirals during a median of 13 years were included. Deep salvage therapy included darunavir, tipranavir, etravirine or raltegravir in 4, 2, 2 and 5 subjects, respectively. Self-reported treatment adherence was adequate in 4 and partial in 2; one individual underwent treatment interruption during follow-up. Deep sequencing detected all mutations found by population sequencing and identified additional resistance mutations in all but one individual, predominantly after virological failure to deep salvage therapy. Additional genotypic information led to consistent decreases in predicted susceptibility to etravirine, efavirenz, nucleoside reverse transcriptase inhibitors and indinavir in 2, 1, 2 and 1 subject, respectively. Deep sequencing data did not consistently modify the susceptibility predictions achieved with population sequencing for darunavir, tipranavir or raltegravir. CONCLUSIONS: In this subset of heavily pre-treated individuals, deep sequencing improved the assessment of genotypic resistance to etravirine, but did not consistently provide additional information on darunavir, tipranavir or raltegravir susceptibility. These data may inform the design of future studies addressing the clinical value of minority drug-resistant variants in treatment-experienced subjects.

Parental occupational exposure to organic solvents and anencephaly in Mexico

Objective: To assess the relationship between parental occupational exposure to organic solvents, and the risk of anencephaly in Mexico. Methods: A case-control study was conducted based on the registers of the Epidemiological Surveillance System for Neural Tube Defects in Mexico; 151 cases of anencephaly of ≥20 weeks’ gestation were included. A control, born alive and without any apparent congenital malformations at birth, was selected for each case in the same maternity service in which the case was born. Information on occupational exposures, lifestyle habits, reproductive history, use of medicines, supplementation with multivitamins and folic acid, was obtained by a general questionnaire; a food frequency questionnaire was also applied to obtain information of daily intake of folate and other B vitamins. Occupational exposure to organic solvents was based on job title as a proxy for exposure and analysed considering two critical periods around conception. Results: In logistic regression analysis, the odds of having a child with anencephaly was higher if the mother or the father was occupationally exposed to organic solvents during the periconceptional period, or when both parents or at least one of them were occupationally exposed during this period with an adjusted odds ratio of 2.97 (95% CI 1.36 to 6.52). Conclusions: The results support the hypothesis that both maternal and paternal occupational exposure to organic solvents can increase the probability of having a child with anencephaly.

Identifying pesticide use patterns among flower growers to assess occupational exposure to mixtures

Objectives Exposure assessment to a single pesticide does not capture the complexity of the occupational exposure. Recently, pesticide use patterns analysis has emerged as an alternative to study these exposures. The aim of this study is to identify the pesticide use pattern among flower growers in Mexico participating in the study on the endocrine and reproductive effects associated with pesticide exposure. Methods A cross-sectional study was carried out to gather retrospective information on pesticide use applying a questionnaire to the person in charge of the participating flower growing farms. Information about seasonal frequency of pesticide use (rainy and dry) for the years 2004 and 2005 was obtained. Principal components analysis was performed. Results Complete information was obtained for 88 farms and 23 pesticides were included in the analysis. Six principal components were selected, which explained more than 70% of the data variability. The identified pesticide use patterns during both years were: 1. fungicides benomyl, carbendazim, thiophanate and metalaxyl (both seasons), including triadimephon during the rainy season, chlorotalonyl and insecticide permethrin during the dry season; 2. insecticides oxamyl, biphenthrin and fungicide iprodione (both seasons), including insecticide methomyl during the dry season; 3. fungicide mancozeb and herbicide glyphosate (only during the rainy season); 4. insecticides metamidophos and parathion (both seasons); 5. insecticides omethoate and methomyl (only rainy season); and 6. insecticides abamectin and carbofuran (only dry season). Some pesticides do not show a clear pattern of seasonal use during the studied years. Conclusions The principal component analysis is useful to summarise a large set of exposure variables into smaller groups of exposure patterns, identifying the mixtures of pesticides in the occupational environment that may have an interactive effect on a particular health effect.

Association analysis of urotensin II gene (UTS2) and flanking regions with biochemical parameters related to insulin resistance.

Background. Urotensin II (UII) is a potent vasoconstrictor peptide, which signals through a G-protein coupled receptor (GPCR) known as GPR14 or urotensin receptor (UTR). UII exerts a broad spectrum of actions in several systems such as vascular cell, heart muscle or pancreas, where it inhibits insulin release. Objective. Given the reported role of UII in insulin secretion, we have performed a genetic association analysis of the UTS2 gene and flanking regions with biochemical parameters related to insulin resistance (fasting glucose, glucose 2 hours after a glucose overload, fasting insulin and insulin resistance estimated as HOMA). Results and Conclusions. We have identified several polymorphisms associated with the analysed clinical traits, not only at the UTS2 gene, but also in thePER3 gene, located upstream from UTS2. Our results are compatible with a role for UII in glucose homeostasis and diabetes although we cannot rule out the possibility that PER3 gene may underlie the reported associations.

Safety and Effectiveness of two treatment regimes with tranexamic acid to minimize inflammatory response in elective cardiopulmonary bypass patients: a randomized double-blind, dose-dependent, phase IV clinical trial

Background. In cardiopulmonary bypass (CPB) patients, fibrinolysis may enhance postoperative inflammatory response. We aimed to determine whether an additional postoperative dose of antifibrinolytic tranexamic acid (TA) reduced CPB-mediated inflammatory response (IR). Methods. We performed a randomized, double-blind, dose-dependent, parallel-groups study of elective CPB patients receiving TA. Patients were randomly assigned to either the single-dose group (40 mg/Kg TA before CPB and placebo after CPB) or the double-dose group (40 mg/Kg TA before and after CPB). Results. 160 patients were included, 80 in each group. The incident rate of IR was significantly lower in the double-dose-group TA2 (7.5% vs. 18.8% in the single-dose group TA1; P = 0.030). After adjusting for hypertension, total protamine dose and temperature after CPB, TA2 showed a lower risk of IR compared with TA1 [OR: 0.29 (95% CI: 0.10-0.83), (P = 0.013)]. Relative risk for IR was 2.5 for TA1 (95% CI: 1.02 to 6.12). The double-dose group had significantly lower chest tube bleeding at 24 hours [671 (95% CI 549-793 vs. 826 (95% CI 704-949) mL; P = 0.01 corrected-P significant] and lower D-dimer levels at 24 hours [489 (95% CI 437-540) vs. 621(95% CI: 563-679) ng/mL; P = 0.01 corrected-P significant]. TA2 required lower levels of norepinephrine at 24 h [0.06 (95% CI: 0.03-0.09) vs. 0.20(95 CI: 0.05-0.35) after adjusting for dobutamine [F = 6.6; P = 0.014 corrected-P significant]. We found a significant direct relationship between IL-6 and temperature (rho = 0.26; P < 0.01), D-dimer (rho = 0.24; P < 0.01), norepinephrine (rho = 0.33; P < 0.01), troponin I (rho = 0.37; P < 0.01), Creatine-Kinase (rho = 0.37; P < 0.01), Creatine Kinase-MB (rho = 0.33; P < 0.01) and lactic acid (rho = 0.46; P < 0.01) at ICU arrival. Two patients (1.3%) had seizure, 3 patients (1.9%) had stroke, 14 (8.8%) had acute kidney failure, 7 (4.4%) needed dialysis, 3 (1.9%) suffered myocardial infarction and 9 (5.6%) patients died. We found no significant differences between groups regarding these events. Conclusions. Prolonged inhibition of fibrinolysis, using an additional postoperative dose of tranexamic acid reduces inflammatory response and postoperative bleeding (but not transfusion requirements) in CPB patients. A question which remains unanswered is whether the dose used was ideal in terms of safety, but not in terms of effectiveness.

Bacteremia due to extended-spectrum beta-lactamase-producing Escherichia coli in the CTX-M era: a new clinical challenge.

Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli, particularly those producing CTX-M types of ESBL, are emerging pathogens. Bacteremia caused by these organisms represents a clinical challenge, because the organisms are frequently resistant to the antimicrobials recommended for treatment of patients with suspected E. coli sepsis. METHODS:A cohort study was performed that included all episodes of bloodstream infection due to ESBL-producing E. coli during the period from January 2001 through March 2005. Data on predisposing factors, clinical presentation, and outcome were collected. ESBLs were characterized using isoelectric focusing, polymerase chain reaction, and sequencing. RESULTS: Forty-three episodes (8.8% of cases of bacteremia due to E. coli) were included; 70% of the isolates produced a CTX-M type of ESBL. The most frequent origins of infection were the urinary (46%) and biliary tracts (21%). Acquisition was nosocomial in 21 cases (49%), health care associated in 14 cases (32%), and strictly community acquired in 8 cases (19%). Thirty-eight percent and 25% of patients had obstructive diseases of the urinary and biliary tracts, respectively, and 38% had recently received antimicrobials. Nine patients (21%) died. Compared with beta-lactam/beta-lactamase-inhibitor and carbapenem-based regimens, empirical therapy with cephalosporins or fluoroquinolones was associated with a higher mortality rate (9% vs. 35%; P=.05) and needed to be changed more frequently (24% vs. 78%; P=.001). CONCLUSIONS: ESBL-producing E. coli is a significant cause of bloodstream infection in hospitalized and nonhospitalized patients in the context of the emergence of CTX-M enzymes. Empirical treatment of sepsis potentially caused by E. coli may need to be reconsidered in areas where such ESBL-producing isolates are present.

Good clinical and cost outcomes using dexrazoxane to treat accidental epirubicin extravasation

A 75-year-old man diagnosed with lower esophageal adenocarcinoma suffered from epirubicin extravasation during the second cycle of neoadjuvant chemotherapy with epirubicin and oxaliplatin. A full recovery was achieved after treatment with dexrazoxane (Cardioxane® ). This is the first time in our hospital that extravasation of an anthracycline has been treated with dexrazoxane. We used Cardioxane® , approved for the prevention of anthracycline-induced cardiotoxicity, while Savene® is indicated for the treatment of anthracycline extravasation. The treatment was effective, and the selection of Cardioxane® (seven-fold cheaper than Savene® ) yielded a cost saving. Consequently, Cardioxane® has been included in our guidelines for anthracycline extravasation.

Oxidative stress is increased in critically ill patients according to antioxidant vitamins intake, independent of severity: a cohort study

Introduction. Critically ill patients suffer from oxidative stress caused by reactive oxygen species (ROS) and reactive nitrogen species (RNS). Although ROS/RNS are constantly produced under normal circumstances, critical illness can drastically increase their production. These patients have reduced plasma and intracellular levels of antioxidants and free electron scavengers or cofactors, and decreased activity of the enzymatic system involved in ROS detoxification. The pro-oxidant/antioxidant balance is of functional relevance during critical illness because it is involved in the pathogenesis of multiple organ failure. In this study the objective was to evaluate the relation between oxidative stress in critically ill patients and antioxidant vitamin intake and severity of illness. Methods. Spectrophotometry was used to measure in plasma the total antioxidant capacity and levels of lipid peroxide, carbonyl group, total protein, bilirubin and uric acid at two time points: at intensive care unit (ICU) admission and on day seven. Daily diet records were kept and compliance with recommended dietary allowance (RDA) of antioxidant vitamins (A, C and E) was assessed. Results. Between admission and day seven in the ICU, significant increases in lipid peroxide and carbonyl group were associated with decreased antioxidant capacity and greater deterioration in Sequential Organ Failure Assessment score. There was significantly greater worsening in oxidative stress parameters in patients who received antioxidant vitamins at below 66% of RDA than in those who received antioxidant vitamins at above 66% of RDA. An antioxidant vitamin intake from 66% to 100% of RDA reduced the risk for worsening oxidative stress by 94% (ods ratio 0.06, 95% confidence interval 0.010 to 0.39), regardless of change in severity of illness (Sequential Organ Failure Assessment score). Conclusion. The critical condition of patients admitted to the ICU is associated with worsening oxidative stress. Intake of antioxidant vitamins below 66% of RDA and alteration in endogenous levels of substances with antioxidant capacity are related to redox imbalance in critical ill patients. Therefore, intake of antioxidant vitamins should be carefully monitored so that it is as close as possible to RDA.

Immune Microenvironment in Colorectal Cancer: A New Hallmark to Change Old Paradigms

Impact of immune microenvironment in prognosis of solid tumors has been extensively studied in the last few years. Specifically in colorectal carcinoma, increased knowledge of the immune events around these tumors and their relation with clinical outcomes have led to consider immune microenvironment as one of the most important prognostic factors in this disease. In this review we will summarize and update the current knowledge with respect to this intriguing and complex new hallmark of cancer, paying special attention to infiltration by T-infiltrating lymphocytes and their subtypes in colorectal cancer, as well as its eventual clinical translation in terms of long-term prognosis. Finally, we suggest some possible investigational approaches based on combinatorial strategies to trigger and boost immune reaction against tumor cells.

Exposure to Trihalomethanes through Different Water Uses and Birth Weight, Small for Gestational Age, and Preterm Delivery in Spain

BACKGROUND Evidence associating exposure to water disinfection by-products with reduced birth weight and altered duration of gestation remains inconclusive. OBJECTIVE We assessed exposure to trihalomethanes (THMs) during pregnancy through different water uses and evaluated the association with birth weight, small for gestational age (SGA), low birth weight (LBW), and preterm delivery. METHODS Mother-child cohorts set up in five Spanish areas during the years 2000-2008 contributed data on water ingestion, showering, bathing, and swimming in pools. We ascertained residential THM levels during pregnancy periods through ad hoc sampling campaigns (828 measurements) and regulatory data (264 measurements), which were modeled and combined with personal water use and uptake factors to estimate personal uptake. We defined outcomes following standard definitions and included 2,158 newborns in the analysis. RESULTS Median residential THM ranged from 5.9 μg/L (Valencia) to 114.7 μg/L (Sabadell), and speciation differed across areas. We estimated that 89% of residential chloroform and 96% of brominated THM uptakes were from showering/bathing. The estimated change of birth weight for a 10% increase in residential uptake was -0.45 g (95% confidence interval: -1.36, 0.45 g) for chloroform and 0.16 g (-1.38, 1.70 g) for brominated THMs. Overall, THMs were not associated with SGA, LBW, or preterm delivery. CONCLUSIONS Despite the high THM levels in some areas and the extensive exposure assessment, results suggest that residential THM exposure during pregnancy driven by inhalation and dermal contact routes is not associated with birth weight, SGA, LBW, or preterm delivery in Spain.

Human Exposure to Endocrine-Disrupting Chemicals and Prenatal Risk Factors for Cryptorchidism and Hypospadias: A Nested Case-Control Study

BACKGROUND. Exposure to xenoestrogens during pregnancy may disturb the development and function of male sexual organs. OBJECTIVE. In this study we aimed to determine whether the combined effect of environmental estrogens measured as total effective xenoestrogen burden (TEXB) is a risk factor for male urogenital malformations. METHODS. In a case-control study, nested in a mother-child cohort (n = 702) established at Granada University Hospital, we compared 50 newborns with diagnosis of cryptorchidism and/or hypospadias with 114 boys without malformations matched by gestational age, date of birth, and parity. Controls did not differ from the total cohort in confounding variables. TEXB and levels of 16 organochlorine pesticides were measured in placenta tissues. Characteristics of parents, pregnancy, and birth were gathered by questionnaire. We used conditional and unconditional regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS. TEXB from organohalogenated compounds was detectable in 72% and 54% of case and control placentas, respectively. Compared with controls, cases had an OR for detectable versus non-detectable TEXB of 2.82 (95% CI, 1.10-7.24). More pesticides were detected in cases than in controls (9.34 +/- 3.19 vs. 6.97 +/- 3.93). ORs for cases with detectable levels of pesticides, after adjusting for potential confounders in the conditional regression analysis, were o,p'-DDT (OR = 2.25; 95% CI, 1.03-4.89), p,p'-DDT (OR = 2.63; 95% CI, 1.21-5.72), lindane (OR = 3.38; 95% CI, 1.36-8.38), mirex (OR = 2.85; 95% CI, 1.22-6.66), and endosulfan alpha (OR = 2.19; 95% CI, 0.99-4.82). Engagement of mothers in agriculture (OR = 3.47; 95% CI, 1.33-9.03), fathers' occupational exposure to xenoestrogens (OR = 2.98; 95% CI, 1.11-8.01), and history of previous stillbirths (OR = 4.20; 95% CI, 1.11-16.66) were also associated with risk of malformations. CONCLUSIONS We found an increased risk for male urogenital malformations related to the combined effect of environmental estrogens in placenta.

Residential Exposure to Outdoor Air Pollution during Pregnancy and Anthropometric Measures at Birth in a Multicenter Cohort in Spain

BACKGROUND. A growing body of research suggests that prenatal exposure to air pollution may be harmful to fetal development. We assessed the association between exposure to air pollution during pregnancy and anthropometric measures at birth in four areas within the Spanish Children's Health and Environment (INMA) mother and child cohort study. METHODS. Exposure to ambient nitrogen dioxide (NO2) and benzene was estimated for the residence of each woman (n = 2,337) for each trimester and for the entire pregnancy. Outcomes included birth weight, length, and head circumference. The association between residential outdoor air pollution exposure and birth outcomes was assessed with linear regression models controlled for potential confounders. We also performed sensitivity analyses for the subset of women who spent more time at home during pregnancy. Finally, we performed a combined analysis with meta-analysis techniques. RESULTS. In the combined analysis, an increase of 10 µg/m3 in NO2 exposure during pregnancy was associated with a decrease in birth length of -0.9 mm [95% confidence interval (CI), -1.8 to -0.1 mm]. For the subset of women who spent ≥ 15 hr/day at home, the association was stronger (-0.16 mm; 95% CI, -0.27 to -0.04). For this same subset of women, a reduction of 22 g in birth weight was associated with each 10-µg/m3 increase in NO2 exposure in the second trimester (95% CI, -45.3 to 1.9). We observed no significant relationship between benzene levels and birth outcomes. CONCLUSIONS. NO2 exposure was associated with reductions in both length and weight at birth. This association was clearer for the subset of women who spent more time at home.

Long-term efficacy and tolerability of flutamide combined with oral contraception in moderate to severe hirsutism: A 12-month, double-blind, parallel clinical trial

OBJECTIVE Our objective was to test the efficacy and tolerability of three doses of flutamide (125, 250, and 375 mg) combined with a triphasic oral contraceptive (ethynylestradiol/levonorgestrel) during 12 months to treat moderate to severe hirsutism in patients with polycystic ovary syndrome or idiopathic hirsutism. DESIGN We conducted a randomized, double-blind, placebo-controlled, parallel clinical trial. PATIENTS A total of 131 premenopausal women, suffering from moderate to severe hirsutism, were randomized to placebo or 125, 250, or 375 mg flutamide daily associated with a triphasic oral contraceptive pill. Hirsutism (Ferriman-Gallwey), acne and seborrhea (Cremoncini), and hormone serum levels were monitored at baseline and at 3 (except hormone serum levels), 6, and 12 months. Side effects and biochemical, hematological, and hepatic parameters were assessed. METHODS We used three-way ANOVA (subject, dose, and visit) with Scheffé adjustment for multiple comparisons or nonparametrical Friedman test and least-squares mean (paired data) and Kruskall-Wallis test for unpaired data analyses. We used chi(2) or Fisher's test for categorical data. RESULTS A total of 119 patients were included in the intention-to-treat analysis. All flutamide doses induced a significant decrease in hirsutism, acne, and seborrhea scores after 12 months compared with placebo without differences among dose levels. Similar related side effects were observed with placebo and 125 mg flutamide (12.5%), and slightly higher with 250 mg (17.3%) and 375 mg (21.2%). No statistically significant differences were observed either among doses or compared with placebo. CONCLUSIONS Flutamide at 125 mg daily during 12 months was the minimum effective dose to diminish hirsutism in patients with polycystic ovary syndrome or with idiopathic hirsutism.

Omega 3 fatty acids induce a marked reduction of apolipoprotein B48 when added to fluvastatin in patients with type 2 diabetes and mixed hyperlipidemia: a preliminary report

BACKGROUND Mixed hyperlipidemia is common in patients with diabetes. Statins, the choice drugs, are effective at reducing lipoproteins that contain apolipoprotein B100, but they fail to exert good control over intestinal lipoproteins, which have an atherogenic potential. We describe the effect of prescription omega 3 fatty acids on the intestinal lipoproteins in patients with type 2 diabetes who were already receiving fluvastatin 80 mg per day. METHODS Patients with type 2 diabetes and mixed hyperlipidemia were recruited. Fasting lipid profile was taken when patients were treated with diet, diet plus 80 mg of fluvastatin and diet plus fluvastatin 80 mg and 4 g of prescription omega 3 fatty acids. The intestinal lipoproteins were quantified by the fasting concentration of apolipoprotein B48 using a commercial ELISA. RESULTS The addition of 4 g of prescription omega 3 was followed by significant reductions in the levels of triglycerides, VLDL triglycerides and the triglyceride/HDL cholesterol ratio, and an increase in HDL cholesterol (P < 0.05). Fluvastatin induced a reduction of 26% in B100 (P < 0.05) and 14% in B48 (NS). However, the addition of omega 3 fatty acids enhanced this reduction to 32% in B100 (NS) and up to 36% in B48 (P < 0.05). CONCLUSION Our preliminary findings therefore suggest an additional benefit on postprandial atherogenic particles when omega 3 fatty acids are added to standard treatment with fluvastatin.